Autoimmune diseases comprise the third most common category of illness in the United States affecting an estimated 22 million Americans. To date, therapeutic and preventive strategies for human autoimmune diseases (based on the restoration of immune tolerance) have been largely disappointing. Experimental animal models greatly facilitate the study of the pathogenesis and complications of autoimmune disease. They permit the evaluation of treatment protocols that pose ethical issues and safety risks in humans. They provide populations of genetically identical subjects that can be maintained under controlled environmental conditions. With them, new pharmaceutical agents, dietary regimens etc. can be tested to determine therapeutic benefit while detecting potential toxicity and unanticipated worsening of disease prior to human application. Preclinical testing of new agents and diets therefore represents a multimillion-dollar commercial market that would embrace a new, well-characterized rat model of multiple autoimmune diseases including, especially, T1D and rheumatoid arthritis. In our preliminary studies we report that LEW.1WR1 rats are 1) susceptible to virus-triggered autoimmune diabetes and experimental allergic encephalomyelitis, 2) susceptible to adjuvant arthritis, and 3) can develop diabetes during treatment to induce arthritis. These characteristics make the LEW.1WR1 rat an attractive commercial candidate for a test bed for studying both the efficacy of therapies for autoimmune disease prevention and reversal as well as screening for unanticipated adverse effects that would compromise the safety of such medications. We are therefore requesting funding to enhance the drug-platform-testing utility and commercial value of the LEW.1WR1 rat model of autoimmune diseases. In Phase 1 we will fully evaluate the autoimmune susceptibilities of these animals in response to perturbation of innate immunity and viral infection. In Phase 2, we will identify the genetic basis of the susceptibility of LEW.1WR1 rats to the different forms of autoimmunity characterized in Phase 1. Our specific aims are: 1: Identify the immunological and viral perturbants that increase the penetrance of disease in the LEW.1WR1 rat model of type 1 diabetes 2. Establish the LEW.1WR1 rat as a model of rheumatoid arthritis 3. Determine if the diabetic LEW.1WR1 rat develops thyroiditis, celiac disease, adrenal insufficiency, and sialadentis for use as a model of these disorders. PUBLIC HEALTH RELEVANCE: No preventative or curative therapies have been identified for the multiple autoimmune diseases that affect 22 million Americans. Progress in the development of new therapeutics is hampered by the lack of appropriate animal models. We have identified a novel autoimmune-susceptible rat strain that is poised to develop multiple autoimmune syndromes in response to environmental pertubants. This unique model is ideally suited for science-based preclinical safety evaluation that is needed before new therapies can be tested in humans.